RT Book, Section
A1 Wilkin, Douglas J.
A1 Hecht, Jacqueline T.
A1 Francomano, Clair A.
A2 Valle, David L.
A2 Antonarakis, Stylianos
A2 Ballabio, Andrea
A2 Beaudet, Arthur L.
A2 Mitchell, Grant A.
SR Print(0)
ID 1181476200
T1 Achondroplasia and Pseudoachondroplasia
T2 The Online Metabolic and Molecular Bases of Inherited Disease
YR 2019
FD 2019
PB McGraw-Hill Education
PP New York, NY
SN 9780071459969
LK ommbid.mhmedical.com/content.aspx?aid=1181476200
RD 2024/04/24
AB Achondroplasia  and  pseudoachondroplasia  are  clinically  and  genetically  distinct  phenotypes  that  are  among  the  most  common  human  disorders  resulting  in  short  stature.  Both  are  inherited  as  autosomal  dominant  conditions.  Achondroplasia,  the  single  most  common  form  of  human  dwarfism,  results  in  most  cases  from  one  of  two  very  specific  mutations  in  the  gene  encoding  fibroblast  growth  factor  receptor  3  (FGFR3).  Pseudoachondroplasia  is  caused  by  a  variety  of  mutations  in  the  gene  encoding  cartilage  oligomeric  matrix  protein  (COMP).  Both  disorders  are  characterized  by  short-limb  dwarfism,  in  which  the  affected  person's  arms  and  legs  are  relatively  short  compared  to  the  height  of  the  trunk.  Disorders  with  clinical,  radiographic,  and  molecular  features  in  common  with  achondroplasia  include  hypochondroplasia,  thanatophoric  dysplasia  (TD),  and  severe  achondroplasia  with  developmental  delay  and  acanthosis  nigricans  (SADDAN).  Similarly,  pseudoachondroplasia  and  multiple  epiphyseal  dysplasia  (MED)  are  related.The  clinical  manifestations  of  achondroplasia  include  rhizomelic  short  stature,  frontal  bossing  with  midface  hypoplasia,  short  ribs,  trident  hand,  limited  elbow  extension,  and  hyperextensible  hips  and  knees.  Infants  may  have  a  thoracolumbar  kyphosis  or  gibbus.  Spinal  stenosis  is  a  common  complication  in  adulthood.  Less  frequent  complications  in  childhood  include  cervicomedullary  compression  secondary  to  a  small  foramen  magnum,  hydrocephalus,  and  obstructive  apnea  secondary  to  small  airways.  Age-specific  mortality  is  increased  in  the  first  4  years  of  life  and  in  the  fourth  to  fifth  decades.Homozygous  achondroplasia  is  a  neonatal  lethal  condition  in  which  the  skeletal  manifestations  of  achondroplasia  are  exaggerated.  Death  is  usually  secondary  to  respiratory  compromise  or  from  cervical  cord  compression  by  a  very  small  foramen  magnum.  In  families  where  both  parents  have  achondroplasia,  the  children  are  at  25  percent  risk  of  inheriting  the  achondroplasia  mutation  from  both  parents,  resulting  in  homozygous  achondroplasia.The  phenotype  of  hypochondroplasia  is  similar  to  that  of  achondroplasia  but  milder  in  degree.  The  height  curves  overlap  with  those  of  the  average  population  and  spinal  stenosis  is  infrequently  observed.  Learning  disabilities  may  be  more  common  among  children  with  hypochondroplasia  than  among  children  with  achondroplasia.Thanatophoric  dysplasia  (TD),  a  neonatal  lethal  disorder,  is  the  most  severe  of  the  FGFR3  phenotypes.  Two  types,  designated  TDI  and  TDII,  are  distinguishable  on  clinical  and  molecular  grounds.  The  SADDAN  phenotype  is  a  recently  recognized  condition  in  the  achondroplasia  family  of  disorders.Achondroplasia,  hypochondroplasia,  TDI,  TDII,  and  the  SADDAN  phenotype  are  all  caused  by  mutations  in  the  FGFR3  gene.  All  are  dominant  phenotypes  and  most  cases  occur  as  a  result  of  new  mutation.  Most,  if  not  all,  new  mutations  causing  achondroplasia  occur  on  the  paternal  allele.The  FGFRs  are  a  family  of  four  tyrosine  kinase  receptors.  They  have  three  immunoglobulin-like  regions  in  the  extracellular  domain,  a  transmembrane  domain,  and  a  split  intracellular  tyrosine  kinase  domain.  The  different  receptors  bind  fibroblast  growth  factors  (FGFs)  with  variable  affinity.  Alternative  splicing  is  a  feature  of  FGFR  RNA  processing.  The  receptor  monomers  dimerize,  in  a  step  requiring  heparin,  before  ligand  may  be  bound.  The  dimerization  process  is  promiscuous;  any  FGFR  monomer  may  dimerize  with  any  other.FGFR3  has  two  splice  forms  depending  on  which  of  two  alternative  exons  are  used  for  the  C-terminal  half  of  the  third  immunoglobulin-like  domain.  FGFR3  with  ...